TY - JOUR
AU - Brevini, Teresa
AU - Maes, Mailis
AU - Webb, Gwilym J.
AU - John, Binu V.
AU - Fuchs, Claudia D.
AU - Buescher, Gustav
AU - Wang, Lu
AU - Griffiths, Chelsea
AU - Brown, Marnie L.
AU - Scott III, William E.
AU - Pereyra-Gerber, Pehuén
AU - Gelson, William T.H.
AU - Brown, Stephanie
AU - Dillon, Scott
AU - Muraro, Daniele
AU - Sharp, Jo
AU - Neary, Megan
AU - Box, Helen
AU - Tatham, Lee
AU - Stewart, James
AU - Curley, Paul
AU - Pertinez, Henry
AU - Forrest, Sally
AU - Mlcochova, Petra
AU - Varankar, Sagar S.
AU - Darvish-Damavandi, Mahnaz
AU - Mulcahy, Victoria L.
AU - Kuc, Rhoda E.
AU - Williams, Thomas L.
AU - Heslop, James A.
AU - Rossetti, Davide
AU - Tysoe, Olivia C.
AU - Galanakis, Vasileios
AU - Vila-Gonzalez, Marta
AU - Crozier, Thomas W.M.
AU - Bargehr, Johannes
AU - Sinha, Sanjay
AU - Upponi, Sara S.
AU - Fear, Corrina
AU - Swift, Lisa
AU - Saeb-Parsy, Kourosh
AU - Davies, Susan E.
AU - Wester, Axel
AU - Hagström, Hannes
AU - Melum, Espen
AU - Clements, Darran
AU - Humphreys, Peter
AU - Herriott, Jo
AU - Kijak, Edyta
AU - Cox, Helen
AU - Bramwell, Chloe
AU - Valentijn, Anthony
AU - Illingworth, Christopher J.R.
AU - UK-PBC Research Consortium
AU - Dahman, Bassam
AU - Bastaich, Dustin R.
AU - Ferreira, Raphaella D.
AU - Marjot, Thomas
AU - Barnes, Eleanor
AU - Moon, Andrew M.
AU - Barritt IV, Alfred S.
AU - Gupta, Ravindra K.
AU - Baker, Stephen
AU - Davenport, Anthony P.
AU - Corbett, Gareth
AU - Gorgoulis, Vassilis G.
AU - Buczacki, Simon J.A.
AU - Lee, Joo-Hyeon
AU - Matheson, Nicholas J.
AU - Trauner, Michael
AU - Fisher, Andrew J.
AU - Gibbs, Paul
AU - Butler, Andrew J.
AU - Watson, Christopher J.E.
AU - Mells, George F.
AU - Dougan, Gordon
AU - Owen, Andrew
AU - Lohse, Ansgar W.
AU - Vallier, Ludovic
AU - Sampaziotis, Fotios
PY - 2022
DA - December
TI - FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2
JO - Nature
DO - https://doi.org/10.1038/s41586-022-05594-0
AB - Prevention of SARS-CoV-2 infection through the modulation of viral host receptors, such as ACE21, could represent a new chemoprophylactic approach for COVID-19 complementing vaccination2,3. However, the mechanisms controlling ACE2 expression remain elusive. Here, we identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19-affected tissues, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We demonstrate that UDCA-mediated ACE2 downregulation reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we illustrate that UDCA reduces ACE2 expression in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of liver transplant recipients. In conclusion, we identify a novel function of FXR in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the road for future clinical trials.
PB - Springer Nature
UR - https://eprints.gla.ac.uk/286097/
KW - Coronavirus (COVID-19)
ER